1. Field of the Invention
The present invention relates to a novel process for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, which is a well known antidepressant, citalopram.
2 Discussion of the Background
Citalopram is a selective, centrally acting serotonin (5-hydroxytryptarnine; 5HT) reuptake inhibitor having antidepressant activity. This activity has been described, e.g., in J. Hyttel, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. In EP-A 474 580 it has been disclosed that citalopram is also effective in the treatment of dementia and cerebrovascular disorders.
Citalopram has the following structure: 
Citalopram was first described in DE 2,657,013 corresponding to U.S. Pat. No. 4,136,193. It was prepared by the reaction of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a 3-(N,N-dimethylamino)propyl halide in the presence of a condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by a reaction with cuprous cyanide. The other outlined reaction, in general terms, comprises the ring closure of the 5-bromo dihydroxy compound of formula IV 
in the presence of a dehydrating agent. After the ring closure, the 5-bromo group is replaced by a cyano group using cuprous cyanide. The starting material for the compound of formula IV is obtained from 5-bromophthalide by two successive Grignard reactions.
Another preparation process is described in U.S. Pat. No. 4,650,884. In that process the ring closure of the dihydroxy compound of formula V 
is achieved by dehydration with strong sulfuric acid. The starting material is prepared from 5-cyanophthalide by two successive Grignard reactions.
Other processes for the preparation of citalopram are disclosed in patent applications WO 98/19511, WO 98/19512, WO 98/19513, WO 99/30548, WO 00/12044, WO 00/13648, and WO 00/23431. In U.S. Pat. No. 4,943,590, preparation methods for individual enantiomers of citalopram are disclosed. In the process described, the dihydroxy compound of formula V is first transformed into an ester and ring closure is then achieved in the presence of a base.
In the process described in WO 2000/12044 ring closure of a compound of formula VI 
takes place spontaneously after a reaction with 3-(N,N,-dimethylamino)-propyl magnesium halide. Three different ways to prepare compound VI are described. One of the methods includes protection of (4-cyano-2-hydroxymethylphenyl)-4 -fluorophenyl methanol followed by an oxidation to afford compounds of formula VI. The starting hydroxymethyl alcohol compound can be obtained from a phthalide compound by a Grignard reaction followed by the reduction of the resulting ketone. Another method comprises the reaction of 5-cyanophthalide with 4-fluoromagnesiumhalide followed by the the reaction with R-X, wherein R is C6xe2x80x946 alkyl, acyl, alkylsulfonyl ar arylsulfonyl and X is a leaving group, to afford compound VI. In the reaction of 5-cyanophthalide, the resulting ketone compound can also react with the Grignard reagent used, and undesirable side products are formed. It is also possible that the product forms a cyclic hemiketal which does not react in the following step. The third preparation method for compound VI described in WO 00/12044 can be used for the preparation of the S-enantiomer of citalopram.
The present invention provides novel processes for the preparation of citalopram comprising halogenation of 5-cyanophthalide to afford an acid halogenide compound of formula II wherein X is a halogen, and threafter obtaining citalopram through two successive reactions with suitable organometallic halides or organoboranes according to scheme 1.
The process comprises:
a) halogenation of 5-cyanophthalide, thereby obtaining a compound of formula II 
wherein X is halogen,
b) the reaction of a compound of formula II with an organometallic 4-fluorophenyl halide or 4-fluorophenylborane to afford a compound of formula III 
wherein X is as defined above, and
c) the reaction of a compound of formula II with an organometallic dimethylaminopropyl halide to afford 1-(3-dimethylamino-propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram), which is isolated as the base or a pharmaceutically acceptable salt thereof.
Formation of the halide compound of formula II serves two ends. First, high selectivity of the following reaction is obtained, and second, a leaving group in the benzylic position is introduced, so that ring closure to citalopram occurs spontaneously after treatment with a second Grignard reagent.
The resulting citalopram may be isolated as the base or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention are novel intermediate compounds of formula II and III wherein X is a halogen, preferably chloro or bromo, most preferably chloro.
Still other aspects of the invention are processes for the preparation of said intermediates of formula II and III.
Yet another aspect of the invention relates to an antidepressant pharmaceutical composition comprising citalopram or its pharmaceutically acceptable acid addition salts prepared by the process of the invention.
In the context of the present invention, halogen means chloro, bromo, iodo, or fluoro.
The process of the present invention from 5-cyanophthalide to citalopram via acid halogenide is not described in any of the patents mentioned or in any other publication known.
Surprisingly, it has been found that if 5-cyanophthalide is halogenated, the reaction of the resulting compound of formula II with an organometallic 4-fluorohalide or with a 4-fluorophenyl borane is very selective and the subsequent reaction of a compound of formula III with an organometallic 3-dimethylaminopropyl halide gives citalopram in good yield and purity.
The first step of the process is the halogenation of 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (5-cyanophthalide) to form the compound of formula II where X is halogen, preferably chloro or bromo, most preferably chloro. 
The halogenation can be performed by any suitable method known in the art, e.g., by the reaction with thionyl chloride in the presence of a suitable Lewis acid catalyst and a phase transfer catalyst. Catalysis by N,N-dimethylformamide (DMF) is also possible. Suitable Lewis acid catalysts are, e.g., MgCl2, MgBr2, SnCl2, SnCl4, ZnCl2, TiCl4, AlCl3, FeCl3, BF3Et2O, BF3, BBr3, BCl3, B(OEt)3, B(OMe)3, B(O-iPr)3. Preferably a boron-based Lewis acid catalyst is used. The types of phase transfer catalyst which can be used include halides of aromatic or aliphatic ammonium salts, for example tetramethylammonium chloride, tetrabutylammonium chloride or benzyl triethylammonium chloride, or phosphonium salts, for example butyltriphenylphosphonium chloride or tetraphenylphosphonium chloride. The catalysts are used in an amount of from 0.1 to 20 mol % each, preferably 0.5 to 10 mol %, based on the moles of 5-cyanophthalide. The reaction with the catalysts can be performed without any solvent, but if a solvent is used, any inert, high boiling solvent such as toluene, xylene, chlorobenzene or dichlorobenzene can be used.
The halogenation reagent used can be any suitable reagent used for halogenation, e.g. thionyl chloride, PCl3, PCl5, CCl4 in triphenyl phosphine, oxalyl chloride, or cyanuric chloride in trialkyl amine.
The reagents for preparing the corresponding bromo compound can be, e.g., PBr3, PBr5, PPh3Br2, thionyl bromide, or oxalyl bromide.
The halogenation reagent is used in an amount of from 0.5 to 1000 equivalents (based on cyanophthalide), preferably 1 to 10 equivalents, most preferably 1 to 5 equivalents. The reaction temperature can be from 20 to 150xc2x0 C. or reflux temperature, preferably 80 to 140xc2x0 C., most preferably 100 to 130xc2x0 C. The reaction time is from 0.5 to 15 hours, preferably less than 3 hours.
The reaction will be completed readily, and the conversion is close to 100%. The product can be isolated and purified by suitable methods known in the art or the following step can be performed without purification of compound II. The starting material, 5-cyanophthalide, can be prepared, e.g., as described in Tirouflet, Bull. Soc. Sci. Bretagne, 26, 1951, 35-46.
The advantage of making the acid halogenide is that the subsequent reaction with an organometallic 4-fluorophenyl halide or with 4-fluorophenyl borane is very selective unlike the reaction of the lactone directly with 4-fluorophenylmagnesium halide, where the resulting ketone compound is more reactive than the lactone and undesirable side products are formed.
The second step comprises the reaction of the halide compound of formula II with an organometallic or organoboron reagent to afford the compound of formula III. 
The reagent used is a 4-fluorophenylborane or an organometallic 4-fluorophenyl halide, wherein the metallic component can be Mg, Li, Cu, or Zn, preferably Mg or Cu. Preferably the reagent is a 4-fluorophenylmagnesium halide or a Grignard reagent of a 1-halide substituted 4-fluorobenzene, wherein the halogen component is preferably Cl or Br. Most preferably 4-fluorophenylmagnesium bromide is used. The amount of the reagent used is from 0.5 to 2.5 equivalents, preferably from 1 to 1.5 equivalents, based on the equivalents of the compound of formula II.
The reaction is carried out in an inert organic solvent such as toluene, xylene or commonly used ethers such as tetrahydrofuran, diethylether, di-n-butylether, tetrabutylmethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane or mixtures thereof. The preferred solvents are tetrahydrofaran and ethylene glycol dimethyl ether or their mixtures with toluene. Cu, Ni, Pd, Ti, Fe, or Zn compounds can be used as catalysts. Preferably the reaction is performed without any catalyst. The reaction temperature is xe2x88x9280 to 60xc2x0 C., preferably xe2x88x9220 to 20xc2x0 C. The reaction is selective, and the resulting 4-(4-fluorobenzoyl)-2-halomethyl benzonitrile can be isolated and purified by crystallization or any other suitable method known in the art. The subsequent reaction can also be performed without isolation of the intermediate of formula III.
The final step is the reaction of the compound In with an organometallic 3-dimethylaminopropyl halide whereafter the ring closes spontaneously to afford citalopram. The metallo component of the organometallic 3-dimethylaminopropyl halide reagent used can be Mg, Li, Cu, or Zn, preferably Mg or Cu, most prefereably Mg. Preferably the reagent is a Grignard reagent of a 3-(N,N-dimethylamino)propyl halide, wherein the halide is Cl or Br. Most preferably the reagent is 3-(N,N-dimethylamino)propylmagnesium chloride. The reaction is carried out in an inert organic solvent such as toluene, xylene or commonly used ethers such as tetrahydrofuran, diethylether, di-n-butylether, tetrabutylmethyl ether, ethylene glycol dimethyl ether or 1,4-dioxane or mixtures thereof. The preferred solvents are tetrahydrofaran or ethylene glycol dimethyl ether or their mixtures with toluene. Cu, Ni, Pd, Ti, Fe, or Zn compounds can be used as catalysts. Preferably the reaction is performed without any catalyst. The reaction temperature is xe2x88x9280 to 60xc2x0 C., preferably xe2x88x9220 to 20xc2x0 C., and the reaction time is from 0.5 to 15 hours, preferably less than 3 hours. The organometallic reagent is used in an amount of from 0.5 to 2.5 equivalents, preferably from 0.8 to 1.8 equivalents, based on the equivalents of the compound of formula III.
After the reaction, the ring closes spontaneously affording citalopram. The resulting citalopram can be isolated as a base or a pharmaceutically acceptable salt thereof.
All the reactions from 5-cyanophthalide to citalopram can be performed in one pot which makes the process convenient and saves costs and labour when no isolation or purification processes of intermediates are needed. Another method is to isolate compound II and then perform the following reactions b) and c) in the same pot without the separation of intermediates.
The compound of formula I may be used as a free base or as a pharmaceutically acceptable acid addition salt thereof. The acid addition salts can be prepared by methods known in the art.